One night's total sleep deprivation can induce profound antidepressant effects in depressed patients. Following the absence of sleep for one night, 40-60% of depressed patients typically show the transient onset of mood improvement, which is then lost following a nap or the next night's recovery sleep. Thus, the sleep deprivation paradigm becomes a non-pharmacological means of acutely inducing altered mood states in a fashion that may yield important information about underlying mechanisms. While the mood changes are usually transient they may provide insights into neural systems involved in mood dysregulation and its acute reversal. Some patients show stable degrees of improvement, while others show either tolerance or progressive improvement following repeat sleep deprivation. In rapid-cycling bipolar patients there is a relative refractoriness to sleep deprivation-induced mood improvement early in a depressive episode, but as the episode progresses transient improvement is noted, and toward the end of an episode more dramatic improvement or long-lasting switches out of depression occur. These data suggest that there are differential neurobiological substrates as a function of the temporal phase of bipolar episodes. Sleep deprivation is associated with significant increases in TSH, T3, T4, and free T4. Increases in TSH secretion have been reported correlated with the degree of clinical re- sponse to sleep deprivation in some studies. Our findings do not show consistent statistical significance in most measures, but delta TSH is correlated with degree of self-rated (delta Beck Depression Scores) improvement. As sleep deprivation may remove inhibit-ory control over TSH secretion (possibly at the level of increased TRH) these data are consistent with other suggested alterations in the limbic-hypothalamic- pituitary-thyroid (L-HPT) axis in affective illness. Since Ketter et al have found that relative hypothyroidism (higher TSH) is associated with frontal hypometabolism on PET, and sleep deprivation responders have relative limbic hyperactivity at baseline, it is possible that sleep deprivation removes this inhibitor tone, increasing TSH and helping to correct the frontal defect in metabolism. TRH infusions may also affect the frontal hypometabolism more directly. However, initial analyses suggest that positive response to sleep deprivation is not directly associated with positive response to TRH or to drugs such as carbamazepine, which increases TRH in CSF of our patients.